Timing Liu

Simultaneous Screening of the FRAXA and FRAXE Loci for Rapid Detection of FMR1 CGG and/or AFF2 CCG Repeat Expansions by Triplet-Primed PCR

Publisher: Elsevier BV

Date: 08-2021

DOI: 10.1016/J.JMOLDX.2021.04.015

Abstract: Moderate to hyper-expansion of trinucleotide repeats at the FRAXA and FRAXE fragile sites, with or without concurrent hypermethylation, has been associated with intellectual disability and other conditions. Unlike molecular diagnosis of FMR1 CGG repeat expansions in FRAXA, current detection of AFF2 CCG repeat expansions in FRAXE relies on low-throughput and otherwise inefficient techniques combining Southern blot analysis and PCR. A novel triplet-primed PCR assay was developed for simultaneous screening for trinucleotide repeat expansions at the FRAXA and FRAXE fragile sites, and was validated using archived clinical s les of known FMR1 and AFF2 genotypes. Population s les and FRAXE-affected s les were sequenced for the evaluation of variations in the AFF2 CCG repeat structure. The duplex assay accurately identified expansions at the FMR1 and AFF2 trinucleotide repeat loci. On Sanger sequencing of the AFF2 CCG repeat, the single-nucleotide polymorphism variant rs868914124(C) that effectively adds two CCG repeats at the 5'-end, was enriched in the Malay population and with short repeats (<11 CCGs), and was present in all six expanded AFF2 alleles of this study. All expanded AFF2 alleles contained multiple non-CCG interruptions toward the 5'-end of the repeat. A sensitive, robust, and rapid assay has been developed for the simultaneous detection of expansion mutations at the FMR1 and AFF2 trinucleotide repeat loci, simplifying screening for FRAXA- and FRAXE-associated disorders.

Investigating misclassification of type 1 diabetes in a population-based cohort of British Pakistanis and Bangladeshis using polygenic risk scores

Publisher: Cold Spring Harbor Laboratory

Date: 25-08-2023

DOI: 10.1101/2023.08.23.23294497

Abstract: Correct classification of type 1 (T1D) and type 2 diabetes (T2D) is challenging due to overlapping clinical features and the increasingly early onset of T2D, particularly in South Asians. We used polygenic risk scores (PRSs) in a British Bangladeshi and Pakistani population with diabetes to estimate the proportion and misclassification rate of T1D in insulin-treated in iduals with ambiguous features. Using linked health record from the Genes & Health cohort (n=38,344) we defined four groups: 31 T1D cases, 1,842 T2D cases, and after excluding these, 839 insulin-treated in iduals with ambiguous features and 5,174 controls. Combining these with 307 confirmed T1D cases and 307 controls from India, we calculated ancestry-corrected PRSs for T1D and T2D, with which we estimated the proportion of T1D cases within the ambiguous group and evaluated misclassification. We estimated that the prevalence of T1D was ∼6% within the ambiguous group, or ∼4.5% within the subset who had T2D codes in their health records. We saw no significant association between the T1D or T2D PRS and BMI at diagnosis, time to insulin, or the presence of T1D or T2D diagnostic codes amongst the T2D or ambiguous cases. We estimate that 4.5% of British Pakistanis and Bangladeshis with diabetes who are treated with insulin and have ambiguous clinical features have been classified incorrectly in their health records, and in fact have T1D. These findings have significant implications for the delivery of optimal clinical care at population level.

National Health Service

Location: United Kingdom of Great Britain and Northern Ireland

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Wellcome Sanger Institute

Location: United Kingdom of Great Britain and Northern Ireland

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University Of Cambridge

Location: No location found

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Moorfields Eye Hospital

Location: United Kingdom of Great Britain and Northern Ireland

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University Of Cambridge

Location: United Kingdom of Great Britain and Northern Ireland

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